Sputum concentrations show promise as chronic bronchitis biomarker

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Total airway mucin concentrations may be a quantitative biomarker for the diagnosis of chronic bronchitis and a target for the development of therapy for the disorder, based on newly published research.

Note that chronic bronchitis, which is characterized by chronic cough and sputum production in current and former cigarette smokers, is identified as chronic obtructive pulmonary disease (COPD) when associated with airflow obstruction.

Total airway mucin concentrations show promise as an important biomarker for chronic bronchitis, which is a key component of chronic obstructive pulmonary disease (COPD), new research suggests.

Researchers tested the hypothesis that mucin concentrations are a biochemical hallmark of the pathogenesis of chronic bronchitis in an extensively phenotyped cohort of the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS).

Their findings, published Sept. 6 online in the New England Journal of Medicine, suggest that airway mucin concentrations, "describe a potential disease-causing, chronic-bronchitis pathway that is associated with sputum production and disease severity."

"If replicated, our results suggest that airway mucin concentrations may serve as a biomarker for the confirmation of the diagnosis of chronic bronchitis and the development of therapeutics for the disorder," wrote researcher Mehmet Kesimer, PhD, of the University of North Carolina Cystic Fibrosis Center, Chapel Hill, and colleagues.

They noted that chronic bronchitis -- characterized by chronic cough and sputum production in cigarette smokers and former smokers -- is identified as COPD when associated with airflow obstruction.

"Despite the importance of mucus accumulation in the pathogenesis of chronic bronchitis, a unifying hypothesis that describes the failure of mucus flow with consequent mucus accumulation in chronic bronchitis has been lacking, and there have been no laboratory methods to confirm a diagnosis of chronic bronchitis," the researchers wrote.

In the newly published study, Kesimer and colleagues characterized the COPD status of 917 participants in SPIROMICS using questionnaires administered to participants, chest tomography, spirometry and examination of induced sputum.

Total mucin concentrations in sputum were measured using size-exclusion chromatography and refractometry. The respiratory secreted mucins MUC5AC and MUC5B were quantitated using mass spectrometry in 148 study participants.

Chronic-bronchitis questionnaires and data on total mucin concentrations in sputum were also analyzed in an independent analysis including 94 participants.

The analysis revealed that:

Mean (±SE) total mucin concentrations were higher in current or former smokers with severe COPD than in controls who had never smoked (3,166±402 vs. 1,515±152 μg per milliliter) and were higher in participants with two or more respiratory exacerbations per year (n=36) than in those with zero exacerbations (4,194±878 versus 2,458±113 μg per milliliter).

The absolute concentrations of MUC5B and MUC5AC in current or former smokers with severe COPD were approximately three times as high and 10 times as high, respectively, as in controls who had never smoked.

Receiver-operating-characteristic curve analysis of the association between total mucin concentration and a diagnosis of chronic bronchitis yielded areas under the curve of 0.72 (95% CI, 0.65-0.79) for the SPIROMICS cohort and 0.82 (95% CI, 0.73-0.92) for the independent cohort.

The researchers wrote that the associations between total mucin concentration and the pathogenesis of chronic bronchitis suggest that this metric may be a quantitative biomarker for chronic bronchitis.

"Our results have therapeutic implications for chronic bronchitis," they wrote. "Higher total mucin concentrations (as compared with lower concentrations) were associated with asthma and exposure to cigarette smoke, suggesting that target upstream components of these pathways to inhibit MUC5B and MUC5AC production may be useful."

In an accompanying editorial, Jadwiga Wedzicha, MD, of Imperial College London, wrote that the finding that airway mucins are related to smoking, respiratory symptoms and disease severity and exacerbations, "further consolidates the central role of chronic bronchitis in COPD."

"Airway mucins are a key target for the development of new interventions in COPD," Wedzicha wrote. "Further study is needed to understand the mechanisms of how mucins contribute to the development of airway inflammation and the progression of airflow obstruction."

Wedzicha wrote that while airway mucins show promise as a biomarker for chronic bronchitis, more research is needed "to refine the definition and detection of the disorder."

"However, we now know that chronic bronchitis occurs in middle age in smokers, before airflow obstruction is even detected. Thus, the exciting prospect is that airway mucins may eventually predict who will have disabling symptoms from COPD," Wedzicha wrote.

This research was funded by grants from the National Heart, Lung, and Blood Institute, along with pharmaceutical industry support through the Foundation for the National Institutes of Health.

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